Multiple sclerosis (MS) is a progressive neurological disorder characterized by an autoimmune mediated attack against the myelin sheath surrounding axons in the central nervous system (CNS) resulting in inflammation, demyelination, gliosis and ultimately axonal degeneration (Bruck and Stadelmann, 2003). The clinical course of MS is divided into four major categories (or subtypes): relapsing-remitting (RRMS), secondary-progressive (SPMS), primary progressive (PMS) and progressive relapsing (PRMS). Patients who have clinical relapses every few months or years with intervening periods of clinically stability define RRMS. RRMS is twice more common in females than males in the second or third decade of life (Noseworthy et al., 2000). In contrast to RR MS, patients with SPMS display progressive deterioration between relapses. RRMS patients may convert to SP MS over time characterized by a gradual decline in neurological function (Trojano et al., 2003). Approximately 15% of MS patients have PPMS characterized by late-onset and an unrelenting deterioration of neurological function from disease onset. Benign MS is arbitrarily defined as those RRMS patients who after more than 15 years following initial diagnosis are still mobile and show only mild deficits (Expanded Disability Status Scale [EDSS]≦4). Typically, these patients show little or no progression after their initial attack and require no therapeutic intervention; however, it is not possible to diagnose this form of MS until 5 years from MS onset (Pittock et al., 2004).
Apoptosis is an important mechanism in immune system regulation, responsible for elimination of autoreactive T cells, B cells and macrophages from the circulation and prevention of their entry into the CNS. It has been hypothesized that a failure of autoreactive T lymphocytes and B lymphocytes as well as activated macrophages to undergo apoptosis contributes to the pathogenesis of MS. Consistent with this hypothesis, expression of members of the inhibitors of apoptosis (IAP) family of anti-apoptotic proteins such as XIAP, HIAP-1, and HIAP-2 are elevated in mitogen stimulated T cells from MS patients relative to healthy or neurological control subjects (Seki et al., 1988; Semra et al., 2002; Sharief et al., 2002; Sharief and Semra, 2001; Tsukamoto et al., 1986). In a murine model of experimental autoimmune encephalomyletis XIAP knockdown using an antisense oligonucleotide decreases clinical severity (Zehntner et al., 2005). The goal of current MS therapies is to lengthen the time between relapses and thereby slow or perhaps even halt disease progression in some cases. IFN-β has been shown to lengthen the time between relapses in individuals with MS. IFN-β has been shown to reduce expression of the anti-apoptotic proteins, XIAP, HIAP-1 and HIAP-2 in mitogen stimulated T cells from MS patients suggesting that IFN-β drugs may improve the symptoms of MS by promoting the elimination of autoreactive T cells (Sharief et al., 2002).
IFN-β (Betaseron, Rebif, Avonex or Copaxone) is a very expensive therapy, which produces modest clinical benefits in MS patients. Many MS patients, however, fail to respond to IFN-β. The majority of MS patients are characterized as RRMS (85%), of which over time increasing numbers will convert to SPMS. Approximately 15% of MS patients have PPMS and do not respond to IFN-β. Currently, there are no diagnostic tests that enable a clinician to predict the likelihood of a RRMS or SPMS patient responding to IFN-β. As a result, neurologists must base a diagnosis of MS, and thereafter a decision on how to treat a patient, on neurological tests or expensive MRI scans, the latter of which being useful only in confirming the diagnosis of MS, but not to yield results that correlate with disease subtype of clinical disability. Thus there is a tremendous need for objective diagnostic tests that predict whether a patient has RRMS or SPMS on first presentation of clinical symptoms. Furthermore, given the high cost of IFN-β drugs coupled with the modest reduction in disease progression produced by these drugs, there is an urgent need for reliable, inexpensive and rapid diagnostic tests to ensure the best use of funds available for treating MS. This is especially the case in the U.S. where over 60% of MS patients are treated with these drugs, many of who experience unpleasant drug-related side effect and little clinical benefit particularly PPMS patients, but also many patients with benign MS, RRMS and SPMS.
It would therefore be highly advantageous to develop a reliable, rapid and inexpensive diagnostic test for RRMS or SPMS and IFN-β responsiveness based on specific patterns of basal gene expression in peripheral immune cells.